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Chapter 2 - INCREASED NUCHAL TRANSLUCENCY WITH NORMAL KARYOTYPE

Increased fetal nuchal translucency thickness at 11–14 weeks of gestation is a common phenotypic expression of trisomy 21 and other chromosomal defects1,2. Extensive studies have now established that, in chromosomally normal fetuses, increased nuchal translucency is also associated with a wide range of fetal defects and genetic syndromes.

Figure 1  - Massively increased nuchal translucency thickness in a 13-week chromosomally normal fetus

SMALL SERIES

In the combined data from several small series, on a total of 510 chromosomally normal fetuses with increased nuchal translucency, there were 77 (15%) with defects (Table 1)3–21.

The most commonly seen defects were anencephaly (n = 1), macrocephaly (n = 1), spina bifida (n = 2), holoprosencephaly (n = 1), Dandy–Walker malformation (n = 1), facial cleft (n = 2), agnathia (n = 1), cystic hygromas (n = 1), cardiac defects (n = 17), pentalogy of Cantrell (n = 1), Ivemark syndrome (n = 1), Toriello–Carey syndrome (n = 1), diaphragmatic hernia (n = 2), esophageal atresia (n = 1), duodenal atresia (n = 1), exomphalos (n = 4), megacystis (n = 3), multicystic kidneys (n = 1), polycystic kidneys (n = 3), amnion rupture sequence (n = 1), body stalk anomaly (n = 2), achondrogenesis (n = 1), achondroplasia (n = 2), campomelic dysplasia (n = 1), ectrodactyly-ectodermal dysplasia–cleft palate syndrome (EEC) (n = 1), fetal akinesia deformation sequence (FADS) (n = 3), syringomyelia (n = 1), kyphosis (n = 1), talipes (n = 1), GM1-gangliosidosis (n = 1), Joubert syndrome (n = 1), Meckel–Gruber syndrome (n = 1), myotonic dystrophy (n = 1), Noonan syndrome (n = 5), spinal muscular atrophy (n = 2), Zellweger syndrome (n = 1) and unspecified syndromes (n = 6).

Table 1 - Studies reporting defects in chromosomally normal fetuses with increased nuchal translucency (NT) thickness at 10–14 weeks of gestation. The cut-off of increased NT varied between the studies
THE FETAL MEDICINE FOUNDATION PROJECT

In the multicenter screening project for trisomy 21 by a combination of maternal age and fetal nuchal translucency involving about 100,000 pregnancies1, there were 4116 singleton, chromosomally normal pregnancies with fetal nuchal translucency above the 95th centile for crown–rump length22. This study includes data on the first 565 cases reported by Pandya et al.23 and those on 89 cases which had detailed postnatal follow up24. A wide range of structural defects and genetic syndromes were identified in 161(3.9%) of the cases (Table 2)22.

The patients were subdivided according to nuchal translucency thickness into five groups: 95th centile to 3.4 mm, 3.5–4.4 mm, 4.5–5.4 mm, 5.5–6.4 and equal to or greater than 6.5 mm. The prevalence of fetal abnormalities increased with nuchal translucency thickness: 3 mm, 2.4%; 4 mm, 7.1%; 5 mm, 12.3%; 6 mm, 16.7%; 7 mm 35.6% (Table 2)22. The diagnosis of abnormalities was made by ultrasound examination in mid-pregnancy, or by pathological examination in terminations of pregnancy and intrauterine or neonatal deaths, or by clinical examination and appropriate investigations in live births. In these calculations, we did not include minor defects, such as choroid plexus cysts, pyelectasia, digital abnormalities or cardiac defects that would not require therapy22.

Table 2 - Fetal defects and genetic syndromes identified in the 4116 pregnancies with increased fetal nuchal translucency in The Fetal Medicine Foundation Project22


Pregnancy outcome

In the 4116 pregnancies, there were 3885 live births that survived the neonatal period, 38 neonatal deaths, 74 spontaneous abortions or intrauterine deaths and 77 terminations at the request of the parents, because fetal abnormalities were detected by ultrasonography in the first trimester or at follow-up scans; termination of pregnancy was also performed in 42 cases because of the uncertain prognosis, since a repeat scan 2 weeks after presentation demonstrated persistence or increase in the large translucency (Table 3)22.

Table 3 - Outcome in 4116 pregnancies with increased fetal nuchal translucency in The Fetal Medicine Foundation Project22
FETAL DEFECTS PRESENTING WITH INCREASED NUCHAL TRANSLUCENCY THICKNESS

An increasing number of fetal abnormalities can now be diagnosed by ultrasound examination in early pregnancy. A review of the literature for studies reporting the diagnosis of fetal abnormalities at the 11–14-week scan identified several conditions that were associated with increased nuchal translucency thickness (Table 4)25–57.


Table 4 Case reports and series of fetal abnormalities diagnosed by early ultrasound examination and found to be associated with increased nuchal translucency thickness (NT)

CONSEQUENCES OF INCREASED NUCHAL TRANSLUCENCY

Increased nuchal translucency at the 11–14-week scan is associated with a wide range of fetal abnormalities. The observed prevalence for some of the abnormalities, such as anencephaly, holoprosencephaly, microcephaly, facial cleft, gastroschisis, renal abnormalities, bowel obstruction and spina bifida, may not be different from that in the general population. However, the prevalence of major cardiac defects, diaphragmatic hernia, exomphalos, body stalk anomaly and fetal akinesia deformation sequence appears to be substantially higher than in the general population and it is therefore likely that there is an association between these abnormalities and increased nuchal translucency thickness. Similarly, there may well be an association between increased translucency and a wide range of rare skeletal dysplasias and genetic syndromes that are usually found in less than 1 in 10,000 pregnancies; however, the number of affected cases, both in the present and previous series of fetuses with increased nuchal translucency, is too small for definite conclusions to be drawn.

In addition to the association between increased nuchal translucency thickness and a wide range of fetal abnormalities, the rates of miscarriage and perinatal death increase with nuchal translucency thickness. These data would be useful in counseling parents of affected pregnancies and in alerting sonographers to plan the appropriate follow-up investigations for such pregnancies. However, it should be emphasized to the parents that increased nuchal translucency thickness per se does not constitute a fetal abnormality and, once chromosomal defects have been excluded, about 90% of pregnancies with fetal translucency below 4.5 mm would result in healthy live births; the rates for translucency of 4.5–6.4 mm and 6.5 mm or more are about 80% and 45%, respectively22.

CONDITIONS ASSOCIATED WITH INCREASED NUCHAL TRANSLUCENCY

The fetal abnormalities and genetic syndromes associated with increased nuchal translucency are summarized in Table 5.


Table 5   Conditions associated with increased nuchal translucency

Cardiac defects
Diaphragmatic hernia
Exomphalos
Achondrogenesis type II
Achondroplasia
Asphyxiating thoracic dystrophy
Beckwith-Wiedemann syndrome
Blomstrand osteochondrodysplasia
Body Stalk anomaly
Campomelic dysplasia
EEC syndrome
Fetal akinesia deformation sequence
Fryn syndrome
GM1-gangliosidosis
Hydrolethalus syndrome

Jarcho-Levin syndrome
Joubert syndrome
Meckel-Gruber syndrome
Nance-Sweeney syndrome
Noonan syndrome
Osteogenesis imperfecta type II
Perlman syndrome
Roberts syndrome
Short-rib polydactyly syndrome
Smith-Lemli-Opitz syndrome
Spinal muscular atrophy type 1
Thanatophoric dysplasia
Trigonocephaly 'C' syndrome
VACTERL association
Zellweger syndrome
ECC syndrome, ectrodactyly-ectodermal dysplasia-cleft palate syndrome
CARDIAC DEFECTS

Increased nuchal translucency is of particular importance in its association with major abnormalities of the heart and great arteries. Studies involving pathological examination in both chromosomally abnormal and normal fetuses with increased nuchal translucency at 11–14 weeks have demonstrated a high prevalence of abnormalities of the heart and great arteries58–63. Additionally, there are several case reports or small series on the sonographic diagnosis of cardiac defects at the 11–14-week scan; in a total of 21 fetuses with major cardiac defects, 17 (81%) had increased nuchal translucency25–28. Furthermore, a retrospective study of 1389 chromosomally normal fetuses with increased translucency reported that the prevalence of major cardiac defects increased with translucency thickness; the diagnosis of cardiac defects was made by ultrasound examination in mid-pregnancy, or by pathological examination in terminations of pregnancy and intrauterine or neonatal deaths, or by clinical examination and appropriate investigations in livebirths63.

In The Fetal Medicine Foundation Project (Table 2), the prevalence of major abnormalities of the heart and great arteries was 10 per 1000 and increased exponentially with increasing translucency thickness from about 4 per 1000 for translucency of 95th centile–3.4 mm, 27 per 1000 for translucency of 3.5–4.4 mm, 43 per 1000 for translucency of 4.5–5.4 mm, 63 per 1000 for translucency of 5.5–6.4 mm, and 169 per 1000 for translucency equal to or greater than 6.5 mm22.

A retrospective study of 29 154 chromosomally normal singleton pregnancies identified major defects of the heart and great arteries in 50 cases (these included 18 that were diagnosed antenatally by an ultrasound examination at 16–31 weeks of gestation, 13 that were diagnosed at pathological examination following intrauterine death or termination of pregnancy for conditions other than cardiac defects, and 19 that were diagnosed in live births)64. The prevalence of major cardiac defects increased with nuchal translucency thickness from 0.8 per 1000 for those with translucency below the 95th centile to 63.5 per 1000 for translucency above the 99th centile (Table 6)64.

Table 6 - Prevalence of major defects of the heart and great arteries in chromosomally normal fetuses by nuchal translucency thickness64

Nuchal Translucency (mm)
n
Major cardiac defects
Prevalence (per 1000)

< 95th centile
27.332
22
0,8
> 95th centile3,4
1.507
8
5,3
3,5 - 4,4
208
6
28,9
4,5 - 5,4
66
6
90,9
> 5,5
41
8
195,1
Total
29.154
50
1,7


The distribution of different types of cardiac defects was similar to that described in previous prenatal and postnatal series (Table 7)64. Although increased nuchal translucency was observed with all types of major abnormalities of the heart and great arteries, there was a stronger association with left-sided defects, such as hypoplastic left heart and coarctation of the aorta. The sensitivity, specificity, positive and negative predictive values of nuchal translucency thickness cut-
off of the 95th and 99th centile in the detection of major cardiac defects are shown in Table 8; essentially 40% of all cardiac defects were in the subgroup with translucency above the 99th centile, and 56% were in the subgroup with translucency above the 95th centile64.

Table 7 Detection of specific cardiac defects using increased fetal nuchal translucency thickness64

Nuchal Translucency

Cardiac defect
Total
> 95th centile
> 99 centile

Tetralogy of Fallot
9 (18%)
2 (22%)
2 (22%)
Hypoplastic Left Heart
3 (6%)
2 (67%)
1 (33%)
Transposition of the great arteries
8 (16%)
4 (50%)
3 (38%)
Coarctation of the aorta or aortic stenosis/atresia
10 (20%)
10 (100%)
8 (80%)
Ventricular and atrioventricular septal defects
8 (16%)
4 (50%)
1 (42%)
Other defects
12 (24%)
6 (50%)
5 (42%)
Total
50 (100%)
28 (56%)
20 (40%)


In a prospective study of 398 chromosomally normal fetuses with a nuchal translucency measurement above the 99th centile (equal to or greater than 3.5 mm), specialist fetal echocardiography was carried out65. Major cardiac defects were present in 29 (7.6%) cases and, in 28 of these, the diagnosis was made by antenatal echocardiography. The prevalence of cardiac defects increased from 3% in those with a nuchal translucency of 3.5–5.4 mm to 15% in those with a measurement of 5.5 mm or more.

The clinical implication of these findings is that increased nuchal translucency constitutes an indication for specialist fetal echocardiography. Certainly, the overall prevalence of major cardiac defects in such a group of fetuses (about 2%) is similar to that found in pregnancies affected by maternal diabetes mellitus or with a history of a previously affected offspring, which are well accepted indications for fetal echocardiography. At present, there may not be sufficient facilities for specialist fetal echocardiography to accommodate the potential increase in demand if the 95th centile of nuchal translucency thickness is used as the cut-off for referral. In contrast, a cut-off of the 99th centile would result in only a small increase in workload and, in this population, the prevalence of major cardiac defects would be very high (about 6%).

Table 8 - Sensitivity and specificity of screening for major defects of the heart and great arteries using fetal nuchal translucency64

 
Using 95th centile
Using 99th centile

Sensitivity
56,0% (95% CI: 42,0-70,0)
40,0% (95% CI: 26,0-54,0)
Specificity
93,8% (95% CI: 93,6-94,1)
99,0% (95% CI: 98,9-99,1)
Positive predictive value
1,5% (95% CI: 1,0-2,1)
6,3% (95% CI: 3,7-9,0)
Negative predictive value
99,9% (95% CI: 99,8-100,0)
99,9% (95% CI: 99,8-100,0)

CI, confidence interval    


Patients identified by nuchal translucency scanning as being at high risk for cardiac defects need not wait until 20 weeks for specialist echocardiography. Improvements in the resolution of ultrasound machines have now made it possible to undertake detailed cardiac scanning in the first trimester of pregnancy26,65–68. A specialist scan from 14 weeks can effectively reassure the majority of parents that there is no major cardiac defect. In the cases with a major defect, the early scan can either lead to the correct diagnosis or at least raise suspicions so that follow-up scans are carried out.

DIAPHRAGMATIC HERNIA

This is a sporadic defect with a birth prevalence of about 1 in 4000. In about 50% of affected fetuses, there are associated chromosomal abnormalities or other defects. In those with isolated diaphragmatic hernia, survival after postnatal surgery is about 50%, but the remainder die due to pulmonary hypoplasia and pulmonary hypertension69.


Figure 2 - Stomach in the chest of a 13-week chromosomally normal fetus with diaphragmatic hernia and increasing nuchal translucency thickness
Figure 2

 

In The Fetal Medicine Foundation Project, the prevalence of diaphragmatic hernia (eight in 4116)22, was higher than expected in the general population, suggesting an association between this defect and increased nuchal translucency. This was indeed found to be the case in a multicenter ultrasound screening study for chromosomal defects by a combination of maternal age and fetal nuchal translucency29. In a total of 78,639 pregnancies presumed to be normal chromosomally, there were 19 cases with diaphragmatic hernia, which was diagnosed at the initial or subsequent scans or at birth. At the early scan, the nuchal translucency was increased in 37% of cases of diaphragmatic hernia, including 83% of those that resulted in neonatal death due to pulmonary hypoplasia and in 22% of the survivors29. See Chapter 3 for the pathophysiology of increased nuchal translucency in diaphragmatic hernia.


EXOMPHALOS

This is a sporadic abnormality with a birth prevalence of about 1 in 4000. At 8–10 weeks of gestation, all fetuses demonstrate herniation of the midgut, visualized by ultrasound as a hyperechogenic mass in the base of the umbilical cord; retraction into the abdominal cavity occurs at 10–12 weeks and it is completed by 11 weeks and 5 days31,70,71.

Herniation of the liver diagnosed at 12-13 weeks gestation

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of exomphalos (11 in 4626), was higher than that expected in the general population6,8,17,20,22. Although one study reported that, in fetuses with exomphalos, increased nuchal translucency signifies an underlying chromosomal defect31, it appears that, even in chromosomally normal fetuses with enlarged translucency, the prevalence of exomphalos is about 10 times higher than in the general population.


ACHONDROGENESIS TYPE II

This is a lethal, autosomal recessive skeletal dysplasia with a birth prevalence of about 1 in 40,000. In the second trimester, the characteristic sonographic features of achondrogenesis type II are severe shortening of the limbs, narrow thorax, hypomineralization of the vertebral bodies but normal mineralization of the skull, and hydrops. In achondrogenesis type I, which is more rare and is also autosomal recessive with severe shortening of the limbs, there is poor mineralization of both the skull and vertebral bodies as well as rib fractures.

 
Courtesy from Claude Colin, MD - www.thefetus.net

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition9. Additionally, there are two case reports on the first-trimester sonographic diagnosis of achondrogenesis type II in high-risk pregnancies; both fetuses had increased nuchal translucency and short limbs that were abnormally positioned, with lack of movement32,33.


ACHONDROPLASIA

This autosomal dominant syndrome has a birth prevalence of about 1 in 26,000, but the majority of cases represent new mutations. The characteristic features include short limbs, lumbar lordosis, short hands and fingers, macrocephaly and depressed nasal bridge. Intelligence and life expectancy are normal. Prenatally, limb shortening usually becomes apparent only after 22 weeks of gestation.

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there were two cases with the condition13,21.


ASPHYXIATING THORACIC DYSTROPHY

Asphyxiating thoracic dystrophy or Jeune’s syndrome is an autosomal recessive condition with a birth prevalence of about 1 in 70,000. The characteristic features are narrow chest and rhizomelic limb shortening. There is a variable phenotypic expression and, consequently, the prognosis varies from neonatal death, due to pulmonary hypoplasia, to normal survival. Limb shortening is mild to moderate and this may not become apparent until after 24 weeks of gestation.

In a case report of Jeune’s syndrome, routine ultrasound examination at 14 weeks demonstrated increased nuchal translucency (5.8 mm) and the femur length was on the 5th centile for gestation; repeat ultrasonography at 22 weeks showed a short narrow thorax and the length of all limbs was well below the 5th centile34.

short narrow thorax at 22-23 weeks

 


BECKWITH-WIEDEMANN SYNDROME

This is a usually sporadic and occasionally familial syndrome with a birth prevalence of about 1 in 14,000. It is characterized by macrosomia and hyperplasia and/or hypertrophy of the tongue, kidneys, adrenals, and pancreas, exomphalos and neonatal hypoglycemia and polycythemia. In some cases, there is mental handicap, which is thought to be secondary to inadequately treated hypoglycemia. About 5% of affected individuals develop tumors during childhood, most commonly nephroblastoma and hepatoblastoma.

In The Fetal Medicine Foundation Project (Table 2), one of the fetuses with increased nuchal translucency and exomphalos had Beckwith–Wiedemann syndrome22.

typical omphalocele 12-13 weeks


BLOMSTRAND OSTEOCHONDRODYSPLASIA

This is a rare, lethal, autosomal recessive skeletal dysplasia characterized by severe shortening of all long bones, increased bone density, small oral cavity with protuberant tongue and hemosiderosis of the liver.

In a case report of a 12-week fetus with the syndrome, from a high-risk pregnancy, there was shortening of all limbs, narrow chest and increased nuchal translucency (6.3mm); after termination of the pregnancy, pathological examination demonstrated thickening of periosteal bone of the metaphyses and diaphyses and hemosiderosis of the liver35.


BODY STALK ANOMALY

This lethal, sporadic abnormality, characterized by the presence of a major abdominal wall defect, severe kyphoscoliosis and a rudimentary umbilical cord, has a birth prevalence of about 1 in 15,000. The pathogenesis is uncertain but possible causes include abnormal folding of the trilaminar embryo during the first 4 weeks of development, early amnion rupture with amniotic band syndrome, and early generalized compromise of embryonic blood flow.

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of body stalk anomaly (12 in 4626) was higher than that expected in the general population11,13,22. In a screening study involving ultrasound examinations at 11–14 weeks and 18–20 weeks of gestation in 3991 patients, there were two cases of body stalk anomaly and they were both diagnosed at the early scan; in one of the cases, there was increased nuchal translucency thickness13.


Figure 3
Figure 3  Body stalk anomaly in a 12-week fetus. The lower part of the body is in the celomic cavity and the upper part in the amniotic cavity

 

In a multicenter study for chromosomal defects by nuchal translucency thickness and maternal age, 106,727 fetuses were examined and 14 of these had body stalk anomaly36. The ultrasonographic features were a major abdominal wall defect, severe kyphoscoliosis and a short umbilical cord. In all cases, the upper half of the fetal body was in the amniotic cavity, whereas the lower part was in the celomic cavity, suggesting that early amnion rupture before obliteration of the celomic cavity is a possible cause of the syndrome. Although the nuchal translucency thickness was increased in 71% of the fetuses, the karyotype was normal in all cases36.


CAMPOMELIC DYSPLASIA

This is a rare, lethal, autosomal recessive syndrome characterized by shortening and bowing of the lower limbs, growth deficiency of prenatal onset, large calvarium with disproportionately small face and narrow chest. Some of the affected genetically male individuals show a female phenotype. Patients usually die in the neonatal period from pulmonary hypoplasia. In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition6.

The curvature of the femur is visible, with a significant limb shortening and bowing.

 


ECTRODACTYLY-ECTODERMAL DYSPLASIA-CLEFT PALATE (EEC) SYNDROME

This is a rare autosomal dominant condition with a wide variability in phenotypic expression. It is characterized by ectrodactyly (split hand and foot), facial cleft (lip and/or palate) and ectodermal dysplasia (anomalies of hair, teeth, nails, nasolacrimal ducts and sweat glands).

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition14. Additionally, there is one case report of EEC syndrome presenting with increased nuchal translucency, oligodactyly and umbilical cord cyst at 14 weeks; after termination of pregnancy, pathological examination demonstrated coarctation of the aorta37. There is another case report on the early diagnosis of the syndrome, but the study does not comment on nuchal translucency measurement; routine ultrasound examination at 14 weeks demonstrated lobster-claw deformities of the hands and feet and facial clefting72 . Pathological examination after termination of the pregnancy confirmed the diagnosis. Subsequently, examination of the parents demonstrated no physical abnormalities, but the mother had microdontia of the lateral upper incisors which were crowned at the age of 15 years72.


FETAL AKINESIA DEFORMATION SEQUENCE (FADS)

This is a heterogeneous group of conditions resulting in multiple joint contractures, including bilateral talipes and fixed flexion or extension deformities of the hips, knees, elbows and wrists. This sequence includes congenital lethal arthrogryposis, multiple pterygium and Pena–Shokeir syndromes. Pathological studies have reported that these features are frequently associated with fetal myopathy, neuropathy or an underlying connective tissue abnormality. Prenatal diagnosis is usually made by ultrasonography during the second or third trimesters of pregnancy and is based on the demonstration of the skeletal deformities; in about one-quarter of the cases, there is nuchal edema38.

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of FADS (nine in 4626) was higher than that expected in the general population8,17,22. A case report of a 12-week fetus in a woman with a previous pregnancy affected by FADS reported akinesia, extension of the hips and flexion of the knees; the study did not comment on the measurement of nuchal translucency73.


Figure 4

Figure 4  Photomicrograph of the hands of a fetus with fetal akinesia deformation sequence presenting at 13 weeks with increased nuchal translucency thickness


Hyett et al.38 examined at 11–13 weeks five pregnancies with a previous history of FADS. In three cases with no obvious fetal defects and normal nuchal translucency thickness, there were no abnormal findings at the subsequent scans and healthy infants were delivered at term. In two cases, the fetal nuchal translucency thickness was increased and detailed examination demonstrated bilateral fixed flexion deformities of the hands, wrists, elbows and knees, as well as severe talipes. In both cases, chorionic villus sampling was carried out and the fetal karyotype was normal. These findings, as well as the known association between FADS and nuchal edema or hydrops in the second and third trimesters, suggest that, at least in some of the cases, there is increased nuchal translucency thickness at the 11–14-week scan.


FRYN SYNDROME

This is a usually lethal autosomal recessive disorder with a birth prevalence of about 1 in 15,000. It is characterized by the presence of diaphragmatic hernia, digital defects, coarse face and short webbed neck.

In two case reports on the first-trimester presentation of this syndrome, both fetuses had increased nuchal translucency39,40. In the first case, the fetus had a large nuchal translucency at 12 weeks, which partially resolved by 16 weeks39. At 20 weeks, diaphragmatic hernia, pleural effusions and ascites were detected and the limb measurements were on the 5th centile. At 24 weeks, polyhydramnios developed. The infant died in the neonatal period after delivery at 34 weeks, and pathological examination suggested the diagnosis of Fryn syndrome; there was a large diaphragmatic hernia, short neck with redundant nuchal skin, facial dysmorphism, hypertrichosis and distal digital hypoplasia39. In the second case, there was a family history of Fryn syndrome; at 12 weeks there was a large translucency and, after termination, pathological examination demonstrated facial cleft, pterygia of the upper limbs, syndactyly of the hands, oligodactyly of the feet, atresia of the aortic arch and truncus arteriosus with ventricular septal defect40.


GM1-GANGLIOSIDOSIS

This is a rare, lethal, autosomal recessive condition resulting from beta-galactosidase deficiency. It is characterized by visceromegaly, generalized edema and progressive neurological deterioration, resulting in early and severe retardation of both motor and mental development. Death occurs within the first 10 years of life from chest infections.

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition14.


HYDROLETHALUS SYNDROME

This is a rare, lethal, autosomal recessive condition characterized by hydrocephalus, absent corpus callosum, facial cleft, micrognathia, polydactyly, talipes and cardiac septal defects. The brain hemispheres lie separated from each other at the bottom of the skull and the lateral ventricles open medially into the fluid-filled space between and on the top of the hemispheres.

Ammala and Salonen41 reported the ultrasound diagnosis at 12 weeks in a high-risk pregnancy from Finland, where the condition may be more common. There were abnormal brain structures with mid-line echoes only at the bottom of the skull and a large cyst in the upper posterior part of the brain and talipes; in addition, there was increased nuchal translucency41. In another non-Finnish family at high risk for this syndrome, ultrasound examination at 11 weeks demonstrated increased nuchal translucency, a keyhole defect of the skull in the occipital region and talipes42.


Figure 5
Figure 5  Increased nuchal translucency in a 13-week chromosomally normal fetus with severe micrognathia


JARCHO-LEVIN SYNDROME

This is a heterogeneous disorder that is characterized by vertebral and rib abnormalities. An autosomal recessive type (spondylothoracic dysplasia) is characterized by a constricted, short thorax and lethal respiratory insufficiency in infancy. Another type (spondylocostal dysplasia), in which most cases are autosomal recessive but a few are autosomal dominant, is associated with survival to adult life but with some degree of physical disability. In this type, there are other abnormalities, such as caudal agenesis and diaphragmatic hernia.

In The Fetal Medicine Foundation Project (Table 2), there were two cases of this syndrome; in one the diagnosis was made postnatally and in the other by pathological examination after termination of the pregnancy for severe scoliosis at 12 weeks22. In a report on the sonographic features of the syndrome in three affected fetuses at 12 weeks of gestation, there was misalignment of the cervical spine and ribs; additionally, one of the fetuses had increased nuchal translucency at 12 weeks but this resolved spontaneously by 15 weeks43. In another case report, a fetus with spondylocostal dysplasia presented at 12 weeks with increased nuchal translucency and a large cyst occupying the left abdominal and thoracic cavity; at 14 weeks, it was additionally noted that the fetus had thoracic scoliosis and misalignment of the cervical spine and ribs44. The pregnancy was terminated and pathological examination confirmed the prenatal findings; the abdominal cyst was a grossly distended stomach that had partly herniated into the chest through a large left-sided diaphragmatic hernia.


JOUBERT SYNDROME

This is a rare, lethal, autosomal recessive condition characterized by partial or complete absence of the cerebellar vermis. It is associated with profound mental retardation and developmental delay. Death usually occurs in the first 5 years of life.

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of Joubert syndrome (two in 4626) was higher than that expected in the general population12,22.


MECKEL-GRUBER SYNDROME

This lethal, autosomal recessive condition, with a birth prevalence of about 1 in 10,000, is characterized by the triad of encephalocele, bilateral polycystic kidneys and polydactyly.

In one case report of a fetus with Meckel–Gruber syndrome, there was increased nuchal translucency45, but in another study, reporting on five affected fetuses, none had increased translucency46.

Crown-rump length at 11 weeks
Increased Nuchal translucency and the occipital cephalocele
 
occipital cephalocele

3D scan - occipital cephalocele

polydactyly on the specimen picture
Courtesy from Zurita - 2001 © www.TheFetus.net


NANCE-SWEENEY SYNDROME

This is a very rare, autosomal recessive syndrome characterized by short limbs, vertebral abnormalities, deafness and flat face with depressed nasal bridge. Intelligence and life expectancy are normal.

In The Fetal Medicine Foundation Project (Table 2), there was one case of Nance–Sweeney syndrome presenting with increased nuchal translucency (5 mm) at 11 weeks, which resolved by 20 weeks; the diagnosis of the syndrome was made postnatally24.


NOONAN SYNDROME

This is an autosomal dominant condition with wide variability in expression but about 50% of cases represent new mutations. The birth prevalence is about 1 in 2000. It is characterized by lymphedema, thought to be due to dysplasia of the lymphatic system, short and webbed neck, short stature, heart defects, most commonly pulmonary valve stenosis, shield chest, hypertelorism and low set ears. Life expectancy is probably normal in those individuals without severe heart disease. Mild mental retardation is present in about one-third of cases.

In The Fetal Medicine Foundation Project (Table 2), there was only one case of Noonan syndrome, but, in the other studies on a total of 510 chromosomally normal fetuses with increased nuchal translucency, there were five cases of the syndrome (Table 1)3,7,12,14,19,22.


OSTEOGENESIS IMPERFECTA TYPE II

This is a lethal skeletal dysplasia with a birth prevalence of about 1 in 60,000. The majority of cases are new mutations of the genes encoding for polypeptide chains 1 and 2 of collagen type I. Recurrence (6–7%) is usually due to parental mosaicism (somatic or germ-line), although, in a small number of families, autosomal recessive inheritance has been observed74. In the second trimester, the characteristic sonographic features are short limbs and ribs with multiple fractures and hypomineralization of the skull. Death occurs either prenatally or shortly after birth because of respiratory failure. In high-risk pregnancies, prenatal diagnosis can be made by chorionic villus sampling and DNA analysis or demonstration of abnormal collagen production by cultured fibroblasts.

Makrydimas et al.48 reported two cases of osteogenesis imperfecta type II in low-risk patients presenting with increased nuchal translucency (3.4 mm and 4.4 mm, respectively) at 11 weeks. In the first case, repeat ultrasound examination at 15 weeks showed multiple fractures, shortening of long bones, rib fractures and hypomineralization of the skull. The diagnosis of osteogenesis imperfecta type II was made and this was confirmed radiographically and by pathological examination after termination of the pregnancy. In the second case, there was obvious shortening of all long bones and ribs at the 11-week scan. There are another three reported cases of osteogenesis imperfecta type II diagnosed in the first trimester, by demonstration of short, fractured femurs and hypomineralization of the skull, but in these reports there is no comment on the measurement of nuchal translucency75–77.


PERLMAN SYNDROME

This is a rare, autosomal recessive condition characterized by macrosomia, nephromegaly and depressed nasal bridge. The condition is similar to Beckwith–Wiedemann syndrome but they differ in their facial features. Fetal and neonatal mortality is more than 60% and, in survivors, there is a high incidence of neurodevelopmental delay.

In a case report of Perlmann syndrome, the fetus presented with increased nuchal translucency (5 mm) at 11 weeks, which resolved by 23 weeks49. Serial scans demonstrated progressive macrosomia and enlarged kidneys; delivery was carried out at 32 weeks for macrosomia (birth weight 2.8 kg) and the baby died in the neonatal period.


ROBERTS SYNDROME

This is a rare, autosomal recessive condition characterized by symmetrical limb defects of variable severity (tetraphocomelia), facial cleft, hypertelorism, microcephaly and growth retardation. The condition is associated with the cytogenetic finding of premature centromere separation and puffing.

In a case report of an 11-week affected fetus from a high-risk pregnancy, there was tetraphocomelia and increased nuchal translucency50. Another study on the diagnosis of Roberts syndrome reported short limbs in two fetuses at 10 weeks and tetraphocomelia in a third case at 13 weeks; this study did not examine the possible association with increased nuchal translucency78.


SHORT-RIB POLYDACTYLY SYNDROME

This is a rare, autosomal recessive, lethal skeletal dysplasia, characterized by short limbs, narrow thorax and post-axial polydactyly. Associated anomalies are frequently found, including congenital heart disease, polycystic kidneys and intestinal atresia. Four different types have been recognized. Type I (Saldino–Noonan) has narrow metaphyses; type II (Majewski) has cleft lip and palate and disproportionally shortened tibiae; type III (Naumoff) has wide metaphyses with spurs; type IV (Beemer–Langer) is characterized by median cleft lip, small chest with extremely short ribs, protuberant abdomen with umbilical hernia and ambiguous genitalia in some 46,XY individuals.

In a case report of a 13-week fetus with short-rib polydactyly syndrome type I, from a high-risk pregnancy, a narrow chest, short limbs, polydactyly and increased nuchal translucency were present51.


SMITH-LEMLI-OPITZ SYNDROME

This is an autosomal recessive condition with a birth prevalence of about 1 in 20,000. It is associated with a high perinatal and infant mortality. The features include severe mental retardation, characteristic minor facial anomalies, cleft palate, polydactyly and syndactyly, cardiac defects and, in the male, ambiguous or female external genitalia, and deficiency of the enzyme 7-dehydrocholesterol reductase.

In The Fetal Medicine Foundation Project (Table 2), there were three cases of Smith–Lemli–Opitz syndrome22. In one case, the diagnosis was made postnatally, and, in the second, a chromosomally normal male fetus was found by ultrasonography at 20 weeks to have female external genitalia; examination of cultured skin fibroblasts demonstrated increased levels of 7-dehydrocholesterol53. In the third case, the mother had a previous pregnancy resulting in unexplained neonatal death and the diagnosis of Smith–Lemli–Opitz syndrome in the index pregnancy was made by DNA analysis after chorionic villus sampling for increased (6 mm) nuchal translucency. There are also two case reports on the first-trimester sonographic diagnosis of the condition in high-risk pregnancies and in both cases there was increased nuchal translucency52,54.


SPINAL MUSCULAR ATROPHY TYPE I (WERDNIG-HOFFMANN DISEASE)

This is a lethal, autosomal recessive condition with a birth prevalence of about 1 in 25,000. It is characterized by degeneration of anterior horn cells of the spinal cord and brain stem with subsequent muscular hypotonia and atrophy. The onset of symptoms may be intrauterine with a decrease in fetal movements. Death, which occurs in the first 2 years of life, is usually due to respiratory failure.

There are five reported cases of spinal muscular atrophy type 1 presenting in the first trimester with increased nuchal translucency. In two cases, the diagnosis was made antenatally by chorionic villus sampling in patients with a family history of the condition and the pregnancies were terminated14,55. In the other three cases, the babies died in the neonatal period16,22,56.


THANATOPHORIC DYSPLASIA

This is a sporadic condition with a birth prevalence of about 1 in 10,000. The term derives from the Greek, meaning death-bearing. It is characterized by severe shortening of the limbs which are bowed, narrow thorax with short ribs and enlarged head with prominent forehead; in some cases, there is a cloverleaf skull. The condition is lethal, usually in the neonatal period.

In The Fetal Medicine Foundation Project (Table 2), there was one case of thanatophoric dysplasia presenting with increased nuchal translucency (3 mm) at 11 weeks; severe limb shortening and narrow thorax were detected at 17 weeks22. There is a case report on the first-trimester diagnosis of the condition, by the detection of a narrow chest with short and bowed femurs; there is no comment on nuchal translucency measurement79.


TRIGONOCEPHALY 'C' SYNDROME

This is an extremely rare, autosomal recessive condition characterized by trigonocephaly, short nose, prominent maxilla, joint deformities and loose skin due to hyperelasticity. About half of the affected individuals die in infancy while survivors are severely mentally handicapped with progressive microcephaly.

In The Fetal Medicine Foundation Project (Table 2), there was one case of trigonocephaly ‘C’ syndrome presenting at 13 weeks with increased nuchal translucency (3.3 mm); the diagnosis of the condition was made postnatally22.


VACTERL ASSOCIATION

The acronym VACTERL is used to describe a rare, sporadic association of defects including vertebral abnormalities, anal atresia, cardiac defects, tracheo-esophageal fistula with esophageal atresia, radial and renal defects. The prognosis of each patient depends on the particular combination and severity of the abnormalities present. Mental function is usually normal.

In The Fetal Medicine Foundation Project (Table 2), there were two cases of the syndrome presenting at 12 weeks with increased nuchal translucency (2.8 mm and 3.0 mm, respectively); the diagnosis of VACTERL association was made prenatally in one case and postnatally in the other case22.


ZELLWEGER SYNDROME

This lethal, autosomal recessive syndrome has a birth prevalence of about 1 in 25,000. It is characterized by absence or marked decrease in peroxisomes, resulting in profound muscular hypotonia. Other features include dolichoturricephaly, hypertelorism, cataracts, brain abnormalities, cardiac defects, hepatomegaly, and growth retardation. Death occurs in the first 2 years of life, most commonly due to chest infections and liver failure.

In a case report of Zellweger syndrome, the fetus had increased nuchal translucency (6 mm) at 12 weeks and pericardial effusion at 20 weeks; the diagnosis of the condition was made postnatally57.


Chapter 2 - References

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The 11-14-week scan
Copyright © 2001 by KH Nicolaides, NJ Sebire, RJM Snijders
& RLS Ximenes
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